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1

Successful treatment with adjunctive lacosamide in a patient with long term “drug resistant” focal epilepsy

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Fröscher W., Rauber A.

Journal of Epileptology

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2014

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vol. 22

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issue 1

51-55

EN

Introduction. A significant number of patients suffering from epilepsy prove to be resistant to antiepileptic drugs (AEDs). Recent studies, however, suggest that 10–20% of seemingly drug resistant patients may still become seizure-free under the influence of subsequent dosage modifications. Case report. We report on a young man with cryptogenic focal epilepsy. He had his first seizure at the age of fifteen. His seizure frequency was decreased during the following 11 years. However, seizure-freedom was never achieved even though he was treated with twelve to fourteen different AEDs during this time. Intensive presurgical evaluations did not allow identification of a surgically remediable focus. Adjunctive treatment with lacosamide 400 mg/day was not successful. However, the patient became seizure-free immediately after an increase of the lacosamide dose up to 500 mg/day. The patient is now seizure-free for more than two years based on a combination of 500 mg lacosamide and 350 mg lamotrigine, followed by 550 mg and 250 mg, respectively. Discussion and conclusion. This case report highlights that there is always a chance that modifying the medication can result in a drug-resistant epilepsy patient experiencing a significant reduction of seizures and becoming seizure-free. The decisive step in this example was the off-label prescription of a high dose of lacosamide which the patient tolerated well.

2

Hyperthermia can differentially modulate the repair of doxorubicin-damaged DNA in normal and cancer cells*.

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Blasiak J., Widera K., Pertyński T.

Acta Biochimica Polonica

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2003

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vol. 50

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issue 1

191-195

EN

Hyperthermia can modulate the action of many anticancer drugs, and DNA repair processes are temperature-dependent, but the character of this dependence in cancer and normal cells is largely unknown. This subject seems to be worth studying, because hyperthermia can assist cancer therapy. A 1-h incubation at 37°C of normal human peripheral blood lymphocytes and human myelogenous leukemia cell line K562 with 0.5 μM doxorubicin gave significant level of DNA damage as assessed by the alkaline comet assay. The cells were then incubated in doxorubicin-free repair medium at 37°C or 41°C. The lymphocytes incubated at 37°C needed about 60 min to remove completely the damage to their DNA, whereas at 41°C the time required for complete repair was shortened to 30 min. There was also a difference between the repair kinetics at 37°C and 41°C in cancer cells. Moreover, the kinetics were different in doxorubicin-sensitive and resistant cells. Therefore, hyperthermia may significantly affect the kinetics of DNA repair in drug-treated cells, but the magnitude of the effect may be different in normal and cancer cells. These features may be exploited in cancer chemotherapy to increase the effectiveness of the treatment and reduce unwanted effects of anticancer drugs in normal cells and fight DNA repair-based drug resistance of cancer cells.

3

Potential role of transforming growth factor β1 in drug resistance of tumor cells.

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Stoika R., Yakymovych M., Souchelnytskyi S., Yakymovych I.

Acta Biochimica Polonica

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2003

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vol. 50

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issue 2

497-508

EN

Acquired drug resistance of tumor cells is frequently observed in cancer patients undergoing chemotherapy. We studied murine leukemia L1210 cells sensitive and resistant to the cytotoxic action of cisplatin and showed that cisplatin-resistant leukemia cells were also refractory to TGF β1-dependent growth inhibition and apoptosis. Addressing the question about the mechanisms responsible for the cross-resistance to cisplatin and TGF β1, we found that cisplatin- and TGF β1-resistant L1210 cells possessed a decreased expression of type I TGF β1 receptor, while the expression of type II TGF β1 receptor was not affected. Western blot analysis of Smad proteins 2, 3, 4, 6, and 7, which participate in signal transduction pathway down-stream of the TGF b1 receptors, revealed an increased expression of Smad 6, inhibiting TGF b1 action, only in cisplatin- and TGF β1-resistant L1210 cells. TGF β1 and especially the cytotoxic mistletoe agglutinin increased Smad 6 expression in TGF β1-sensitive but not in TGF β1-resistant L1210 cells. TGF β1-resistant L1210 cells also differed from TGF β1-sensitive cells by the lack of expression of the pro-apoptotic p53 protein and higher level of expression of the anti-apoptotic Bcl-2 protein. Thus, the described co-expression of tumor cell refractoriness to an anti-cancer drug and to the inhibitory cytokine TGF β1 is accompanied by multiple changes in the TGF β1 signal transduction pathway and in other regulatory systems of the target cells. Besides, we found that various anti-tumor drugs and cytotoxic plant lectins increased the level of TGF b1 expression in both TGF β1-sensitive and -resistant L1210 cells. A hypothesis is proposed that TGF β1 can at least partly mediate the effect of cell-stressing agents and, thus, the development of TGF β1 resistance may be responsible for the appearance of tumor cell refractoriness to the action of some anti-cancer drugs.

4

Antifungal drugs resistance profiles of C. albicans strains isolated from the oral cavity of children and adolescents

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Kamińska A., Malm A., Szymańska J.

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2019

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vol. 76

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issue 5

873-876

EN

Fungi, mainly yeast-like fungi of the Candida genus, and especially the species Candida albicans, occupy an important place among microorganisms that colonize the oral cavity. The aim of the paper was to assess the susceptibility of different strains to some antifungal drugs. The study material consisted of swab samples taken from the buccal mucosa of 376 healthy individuals of both genders, from neonate to18 years. C. albicans strains were isolated in 79 persons. To evaluate drug resistance phenotypes of the isolated C. albicans strains FungitestTM (Bio-Rad) was used. The study showed that in different age groups the percentage of the tested C. albicans isolates susceptible to all the tested azole drugs varied from 76% to 95%. Drug resistant strains were found only in the eldest age group (4.8%). Phenotypic diversity (drug resistance types) of the studied isolates indicates a wide range of adaptation possibilities enabling colonization of various ecological niches in the oral cavity ecosystem. The presence of C. albicans strains intermediate or resistant to azole drugs among the tested isolates may be due to overuse of that drug group in general therapy and in the oral cavity treatment.

5

Selected mechanisms of molecular resistance of Candida albicans to azole drugs

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Gołąbek K., Strzelczyk J., Owczarek A., Cuber P., Ślemp-Migiel A., Wiczkowski A.

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issue 2

247-251

EN

A phenomenon of increasing resistance of Candida spp. to azoles has been observed for several years now. One of the mechanisms of lack of sensitivity to azoles is associated with CDR1, CDR2, MRD1 genes (their products are active transport pumps conditioning drug efflux from pathogen's cell), and ERG11 gene (encoding lanosterol 14α-demethylase). Test material was 120 strains of Candida albicans (60 resistant and 60 susceptible to azole drugs) obtained from clinical samples. The first stage of experiment assessed the expression of CDR1, CDR2, MDR1 and ERG11 genes by Q-PCR. The impact of ERG11 gene's mutations on the expression of this gene was analysed. The final stage of the experiment assessed the level of genome methylation of Candida albicans strains. An increase in the expression of CDR2, MDR1 and ERG11 was observed in azole-resistant strains of Candida albicans in comparison to strains sensitive to this class of drugs. Furthermore, 19 changes in the sequence of ERG11 were detected in tested strains. Four of the discovered mutations: T495A, A530C, G622A and A945C led to the following amino acid substitutions: D116E, K128T, V159I and E266D, respectively. It has also been found that statistically five mutations: T462C, G1309A, C216T, C1257T and A945C affected the expression of ERG11. The applied method of assessing the level of methylation of Candida albicans genome did not confirm its role in the development of resistance to azoles. The results indicate however, that resistance of Candida albicans strains to azole drugs is multifactorial.

6

The influence of intracellular idarubicin and daunorubicin levels on drug cytotoxicity in childhood acute leukemia.

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Styczyński J., Wysocki M., Dębski R., Kurylak A., Balwierz W., Rokicka-Milewska R., Matysiak M., Balcerska A., Kowalczyk J., Wachowiak J., Sońta-Jakimczyk D., Chybicka A.

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vol. 49

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issue 1

99-107

EN

Uptake and efflux of two anthracyclines, idarubicin (IDA) and daunorubicin (DNR), was studied in childhood acute leukemia samples. A comparison of IDA and DNR transport phenomena in relation to drug cytotoxicity and expression of P-glycoprotein (PGP) was made. Intracellular content of IDA/DNR was determined by flow cytometry using the fluorescent properties of the drugs. In vitro drug cytotoxicity was measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. PGP expression was analysed by flow cytometry. The uptake and efflux rates were non-significantly higher for IDA than DNR. There were no differences between three types of leukemia with respect to drug content during accumulation and retention. After correction for the cell volume, intracellular concentration of both drugs in each moment of uptake and efflux was significantly lower in relapsed ALL and AML samples in comparison with initial ALL cells. Efflux, but not uptake, of both drugs was inversely correlated with PGP expression and IDA, but not DNR, cytotoxicity. The cytotoxicity was correlated with drug accumulation for both drugs and with drug retention for IDA. In conclusion, it seems that (1) intracellular content was related to the lipophilic properties of the drugs rather than to the type of leukemia, (2) decreased intracellular concentration of both drugs might have an impact on compromised therapy results in AML and relapsed ALL children, (3) IDA presents higher cytotoxicity, which possibly might be decreased by the presence of PGP. These results might have a practical impact on the rational design of new chemotherapy protocols.

7

Leukemic stem cells: from metabolic pathways and signaling to a new concept of drug resistance targeting

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Styczynski J., Drewa T.

Acta Biochimica Polonica

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2007

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vol. 54

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issue 4

717-726

EN

Cancer stem cells are a small subset of cancer cells constituting a reservoir of self-sustaining cells with the exclusive ability to self-renew and maintain the tumor. These cells are identified by specific stem cell markers: antigens, molecules and signaling pathways. Transcription factors and molecules associated with oncogenesis, such as NF-κB, Bmi-1, Notch, WNT beta-catenin, Sonic hedgehog and their biochemical pathways, active only in a small minority of cancer cells might play key roles in determining the biology and the overall long-term behavior of a tumor. The molecules and pathways specific for cancer stem cells, which contribute to their drug resistance, are potential targets for new therapeutic strategies.

8

Antibiotic therapy of acute upper respiratory tract infections and otitis media in adults

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Paź A., Arcimowicz M.

Polski Przegląd Otorynolaryngologiczny

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2018

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vol. 7(1)

1-7

EN

An estimated 50% of antibiotic prescriptions may be unjustified in the outpatient setting. Viruses are responsible for most acute respiratory tract infections. The viral infections are often self-limiting and only symptomatic treatment remains effective. Bacteria are involved in a small percentage of infections etiology in this area. In the case of a justified or documented suspicion of a bacterial infection, antibiotic therapy may be indicated. Based on the Polish „Recommendations for the management of non-hospital respiratory infections 2016”, the indications, the rules of choice, the appropriate dosing schedules and the therapy duration, in the most frequent upper respiratory tract infections in adults, have been presented. Implementation of the presented recommendations regarding our Polish epidemiological situation, will significantly reduce the tendency to abuse antibiotics, and thus will limit the spread of drug-resistant microorganisms.

9

Prevalence and molecular characterization of Salmonella species associated with piglet diarrhea in North East India

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Kylla H., Dutta T. K., Roychoudhury P., Subudhi P. K., Lalsiamthara J.

Polish Journal of Veterinary Sciences

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2019

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issue 4

10

Role of anti-apoptotic pathways activated by BCR/ABL in the resistance of chronic myeloid leukemia cells to tyrosine kinase inhibitors

75%

Danisz K., Blasiak J.

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EN

Chronic myeloid leukemia (CML) is a hematological stem cell disorder characterized by the excessive proliferation of the myeloid lineage. In its initial chronic phase, the myeloid progenitor cells expand and demonstrate apparently normal differentiation. The disease may then transform into the accelerated phase, usually associated with resistance to therapy, and finally, into acute leukemic progression phase - blast crisis. Abnormal myeloid cells produce progenitors, which have lost their ability to differentiate, but retain the capacity to proliferate. The molecular hallmark of CML is the Philadelphia chromosome, resulting from reciprocal chromosome translocation, t(9;22)(q34;q11), and containing the BCR/ABL fusion gene, producing the BCR/ABL protein with a constitutive tyrosine kinase activity. BCR/ABL-positive cells have faster growth and proliferation over their normal counterparts and are resistant to apoptosis. Introduction of imatinib (IM), a tyrosine kinase inhibitor, revolutionized the therapy of CML, changing it from a fatal disease into a chronic disorder. However, some patients show a primary resistance to IM, others acquire such resistance in the course of therapy. Therefore, a small number of leukemic stem cells retains self-renewal capacity under IM treatment. Because BCR/ABL is involved in many signaling pathways, some of them may be essential for resistance to IM-induced apoptosis. The PI3K/AKT, Ras and JAK/STAT signaling pathways are involved in resistance to apoptosis and can be activated by BCR/ABL. Therefore, they can be candidates for BCR/ABL-dependent pro-survival pathway(s), allowing a fraction of CML cells to withstand treatment with tyrosine kinase inhibitors.

11

c-myc Oncogene gene dosage, serum CEA and CA-15.3 antigen levels, and cellular DNA values in relation to ex vivo chemosensitivity of primary human breast cancer.

75%

Falkiewicz B., Schlotter C. M., Bosse U., Bielawski K., Vogt U.

Acta Biochimica Polonica

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2000

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vol. 47

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issue 1

149-156

EN

A pilot study on relationships of selected molecular factors (c-myc oncogene average gene copy numbers (AGCN); serum CEA and CA 15.3 antigen levels; tumor cells' DNA values), to the ex vivo chemosensitivity of primary female human breast cancer in a modified adenosine triphosphate cell viability chemosensitivity assay (ATP-CVA), was performed. Four drug combinations were tested. A group of 75 cases of female primary breast cancer was assessed. Numerous correlations were found among molecular factors tested but none, with the exception of tumor grading, of these reflected ex vivo chemosensitivity of tumors tested. The results suggest that the parameters tested may not be important factors related to adjuvant chemoresponsiveness of primary human breast cancer to tested drug combinations.

12

Występowanie i chorobotwórczość szczepów Enterobacteriaceae – Klebsiella Pneumoniae wytwarzających karbapenemazę klasy b (mbl/ndm) u pacjentów hospitalizowanych i leczonych w mazowieckim szpitalu specjalistycznym w radomiu w latach 2016 – 2018.

63%

Ura L., Deja-Makara B., Pajdziński M., Gottwald L. M.

Long-Term Care Nursing

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2020

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vol. 5

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issue 3

239-249

EN

Aim The aim of the study was to characterize symptomatic infections and asymptomatic carrier of class B carbapenemase (MBL/NDM) produced Klebsiella pneumoniae in patients hospitalized and treated in Mazowiecki Memorial Hospital of Radom between 2016-2018. Material and methods The study group included 120 patients aged 80+/ – 17.0 years old. Epidemiologic analysis of the study group was conducted. Results The number of patients positive towards Klebsiella pneumoniae MBL was: 57 (47,5%) in 2016, 32 (26,6%) in 2017 and 31 (25,8%) in 2018. The study group included 44 women (36,67%) and 76 men (63,33%) (p<0,005). In clinically significant material 60 bacterial strains were identified, with similar frequency from lower respiratory tract discharge and from urine. Symptomatic infections in 60 patients (50%) and asyptomatic carrier in 60 patients (50%) were confirmed. Symptomatic infections from lower respiratory tract were more frequent than urinary tract infections (p=0,037), wound infections (p<0,001), generalized infections (p<0,001) and digestive tract infections (p<0,001). During 2016-2018 reduction in sensitivity of Klebsiella pneumoniae MBL strains for colistin (100%; 46,5%; 45,8%) and amikacin (72,8%; 80,8%; 45,8%) was observed. Conclusions 1. In hospitalized patients positive towards Klebsiella pneumoniae MBL asymptomatic carrier and symptomatic infections occured with similar frequency. 2. In hospitalized patients Klebsiella pneumoniae MBL strains were most frequently identified from respiratory tract and from urinary tract. 3. Commonly with elongation of periode, then colistin and amikacin were used, the reduction of bacterial sensitivity for these antibiotics was observed.

PL

Cel pracy Celem pracy była charakterystyka objawowych zakażeń i bezobjawowego nosicielstwa szczepow Klebsiella pneumoniae wytwarzających karbapenemazę klasy B (MBL/NDM) u pacjentow leczonych na oddziałach szpitalnych Mazowieckiego Szpitala Specjalistycznego (MSS) w Radomiu w latach 2016-2018. Materiał i metody Grupę badaną stanowiło 120 pacjentow w wieku 80 lat +/ – 17,0. Dokonano analizy epidemiologicznej tych przypadkow. Wyniki Stwierdzono 57 przypadkow (47,5%) w 2016 r., 32 (26,6%) w 2017 r. i 31 (25,8%) w 2018 r. pacjentow z obecnością Klebsiella pneumoniae MBL. W grupie badanej były 44 kobiety (36,67%) i 76 mężczyzn (63,33%) (p<0,005). Z materiałow istotnych klinicznie wyhodowano łącznie 60 szczepow Klebsiella pneumoniae MBL. Z podobną częstością izolowano je z wydzieliny z dolnych drog oddechowych oraz z moczu (p=0,436). U 60 pacjentow (50%) stwierdzono zakażenie objawowe, a w 60 przypadkach (50%) wystąpiło bezobjawowe nosicielstwo. Zakażenia dolnych drog oddechowych występowały częściej od zakażeń układu moczowego (p=0,037), zakażeń rany (p<0,001), zakażeń uogolnionych (p<0,001) oraz zakażeń układu pokarmowego (p<0,001). W latach 2016, 2017 i 2018 wykazano zmniejszenie się wrażliwości szczepow Klabsiella pneumoniae MBL na kolistynę (100%; 46,5%; 45,8%) i amikacynę (72,8%; 80,8%; 45,8%). Wnioski 1. Bezobjawowa kolonizacja pacjentow szczepami Klebsiella pneumoniae MBL występuje z podobną częstością do objawowych zakażeń spowodowanych przez te bakterie. 2. Szczepy Klebsiella pneumoniae MBL izolowane są najczęściej z drog oddechowych i moczowych hospitalizowanych pacjentow. 3. Wraz z wydłużeniem okresu stosowania kolistyny i amikacyny w grupie badanej zaobserwowano zmniejszenie wrażliwości szczepow Klebsiella pneumoniae MBL na te antybiotyki.

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Successful treatment with adjunctive lacosamide in a patient with long term “drug resistant” focal epilepsy

Hyperthermia can differentially modulate the repair of doxorubicin-damaged DNA in normal and cancer cells*.

Potential role of transforming growth factor β1 in drug resistance of tumor cells.

Antifungal drugs resistance profiles of C. albicans strains isolated from the oral cavity of children and adolescents

Selected mechanisms of molecular resistance of Candida albicans to azole drugs

The influence of intracellular idarubicin and daunorubicin levels on drug cytotoxicity in childhood acute leukemia.

Leukemic stem cells: from metabolic pathways and signaling to a new concept of drug resistance targeting

Antibiotic therapy of acute upper respiratory tract infections and otitis media in adults

Prevalence and molecular characterization of Salmonella species associated with piglet diarrhea in North East India

Role of anti-apoptotic pathways activated by BCR/ABL in the resistance of chronic myeloid leukemia cells to tyrosine kinase inhibitors

c-myc Oncogene gene dosage, serum CEA and CA-15.3 antigen levels, and cellular DNA values in relation to ex vivo chemosensitivity of primary human breast cancer.

Występowanie i chorobotwórczość szczepów Enterobacteriaceae – Klebsiella Pneumoniae wytwarzających karbapenemazę klasy b (mbl/ndm) u pacjentów hospitalizowanych i leczonych w mazowieckim szpitalu specjalistycznym w radomiu w latach 2016 – 2018.